Converging lines of evidence suggest a cannabinoid hypothesis of schizophrenia that includes exogenous and endogenous elements. According to the better know exogenous hypothesis, 1) cannabinoids can produce a full range of transient schizophrenia-like effects in healthy individuals, 2) cannabinoids can exacerbate psychotic symptoms, trigger relapses and negatively impact the course of illness in schizophrenia patients, and 3) exposure to cannabis may contribute to the risk of developing schizophrenia. Evidence supporting an endogenous hypothesis includes 1) the presence of elevated cerebrospinal fluid (CSF) endocannabinoid levels and 2) post-mortem findings of regional alterations in brain cannabinoid receptors (CB1R) in schizophrenia. Additionally, schizophrenia patients are also more vulnerable to the behavioral and cognitive effects of cannabinoids; a finding that may reflect abnormalities in the endocannabinoid system. The post mortem findings of CB1R availability have been mixed with some studies showing decreases, and others showing increases in different brain regions. Furthermore, the effects of antipsychotic medication on CB1R availability in schizophrenia are not clear, and the relationship between CB1R availability and behavioral and cognitive symptoms in schizophrenia has not been adequately studied. The recent development of several CB1R specific Positron Emission Tomography (PET) ligands, including [11C]OMAR, provide the tools to directly measure CB1R availability in schizophrenia in vivo. Hypothesis: Schizophrenia patients will have lower CB1R availability than controls. Furthermore, unmedicated schizophrenia patients will have lower CB1R availability relative to medicated (antipsychotic- treated) patients. Finally, in schizophreni patients, measures of memory and psychosis will correlate with CB1R availability in hippocampus and ventrostriatal regions, respectively. Aims: To compare CB1R availability in vivo in schizophrenia patients (including a subgroup of patients not taking antipsychotic medications), to age, gender, Body Mass Index (BMI), and smoking status matched healthy controls using the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) PET. In schizophrenia subjects, measures of symptoms and cognition will be correlated to CB1R availability in relevant brain regions. Preliminary Results: We have developed appropriate methods for quantitative analysis of [11C]OMAR data and suggest that [11C]OMAR is an appropriate tracer with which to investigate the CB1R system in humans. Schizophrenia patients have decreased CB1R availability in several brain regions, with the greatest reductions in the pallidum > anterior cingulate cortex > putamen > hippocampus > amygdala. Since the findings were present in subjects who were unmedicated, the observed changes cannot be attributed to the effects of ongoing antipsychotic medications. PUBLIC HEALTH RELEVANCE: The brain cannabinoid receptor system may be altered in schizophrenia. We propose to image brain cannabinoid receptors (CB1R) in individuals with schizophrenia compared to controls. Furthermore, the effects of antipsychotic medications on CB1Rs, and the relationship between CB1Rs and measures of symptoms in individuals with schizophrenia will also be studied.